1. Field of the Invention
The present invention relates generally to the field of cell biology. More specifically, the present invention relates to the prostate-specific membrane antigen-like gene and uses thereof.
2. Description of the Related Art
Prostate cancer is the leading cause of cancer and second leading cause of cancer death among American males. Although prostate tumors in the initial stages are slow growing and can be treated by radical prostatectomy and hormone deprivation, once the tumor is hormone refractory and/or has metastasized, there are few options for the patient. The major current biomarker for this disease is prostate specific antigen (PSA), however PSA is of limited value for assessing patients with disseminated disease as it is down-regulated under conditions of low androgens, and these patients undergo androgen-ablative therapy. More markers for prostate cancer are needed that have increased effectiveness over those currently used for clinical diagnosis and patient management, as well as for future therapeutic targets of this disease.
Prostate specific membrane antigen (PSMA) is an ideal potential target for use in determining patient management, and therapeutic strategies against prostate cancer. The prostate specific membrane antigen is highly expressed in virtually 100% of prostate cancers and, in contrast to PSA, the prostate specific membrane antigen is further upregulated under conditions of androgen deprivation. Furthermore, in the normal prostate, alternative splicing of prostate specific membrane antigen mRNA produces a truncated form of the protein (which has been designated PSM′) that is missing the intracellular and transmembrane domains, and as such, this form is localized to the cytosol [5]. At some stage during tumor initiation or progression, there is a change in the mRNA splicing that leads to the majority of prostate specific membrane antigen transcripts comprising the transmembrane domain, thereby producing a 750 amino acid membrane-bound protein (unlike PSA, which is secreted into the circulatory system), the majority of which is located extracellularly and is readily available for therapeutic targeting, clinical imaging or other diagnostic-type assays [5]. Prostate specific membrane antigen is already used clinically as the target of the imaging agent ProstaScint, and is the focus of a number of therapeutic strategies in development.
The known functions of the prostate specific membrane antigen carboxypeptidase are as an NAALadase and folate hydrolase. Expression of prostate specific membrane antigen is largely confined to the prostate gland, although expression can also be detected in the duodenum brain, salivary gland, kidney, and colon [2,6]. In prostate cancer, enhanced expression of prostate specific membrane antigen correlates with increasing grade of tumor [7].
Additionally, it now seems that therapeutic targeting of the prostate specific membrane antigen molecule may have additional advantages, since prostate specific membrane antigen expression has been found in the endothelial cells of tumor neovasculature of almost all types of tumors examined to date, including bladder, renal, breast and lung carcinomas [1,6]. No prostate specific membrane antigen expression has been found in any kind of normal established non-neovasculature. As such, a therapeutic approach targeted at prostate specific membrane antigen could have broad implications for the treatment of many types of solid tumors, and several groups are now attempting to utilize prostate specific membrane antigen as a treatment target.
However, although prostate specific membrane antigen is very highly expressed in normal prostate (PSM′; the cytosolic form) and in cancer of the prostate (PSMA; the membrane bound form), there are other tissues in the body that express low levels of prostate specific membrane antigen or a similar mRNA, including kidney, proximal small intestine and brain [4]. This mRNA could either be due to expression of the prostate specific membrane antigen gene, or another related gene such as the PSMA-like gene. Furthermore, one of the major enzymes involved in neurotransmission in the brain is NAALADase, which has the same enzymatic characteristics as prostate specific membrane antigen [7]. Accordingly, it is important to be able to distinguish between prostate- or cancer-derived prostate specific membrane antigen and PSMA-like mRNA from other tissues if prostate specific membrane antigen is going to be used as a clinical marker via techniques like RT-PCR or for therapeutic strategies, which, for example, may use antibodies.
Fluorescent in situ hybridization (FISH) mapping using prostate specific membrane antigen cDNA as a probe indicates that there may be two very similar genes both residing on chromosome 11 [8]. Both genes have been mapped against a human-hamster radiation hybrid panel and determined that one of the genes resides on chromosome 11p11.2, while the other gene resides on chromosome 11q14.3 [9]. It was recently determined that the gene on chromosome 11p11.2 is the PSMA gene originally cloned from the prostatic cancer cell line LNCaP [9], while a highly conserved duplication of the PSMA gene, including at least some intronic sequences, is located on chromosome 11q, a region which is known to have been duplicated to chromosome 11p an estimated 22 million years ago [16,17]. Therefore, the so-called non-prostatic expression of the prostate specific membrane antigen gene is due to expression of another highly similar, but distinct gene, herein designated the PSMA-like gene, arising from the aforementioned gene duplication. Tumor targeting for therapeutic approaches or clinical assays relies on the specificity of the marker targeted. As the prostate specific membrane antigen and PSMA-like genes have a common ancestral gene and only diverged from each other 22 million years ago [9], it is likely that the two genes are extremely similar to each other both in sequence and in function.
The prior art is deficient in means of distinguishing between the prostate specific membrane antigen gene and the PSMA-like gene, and their respective protein products. The present invention fulfills this long-standing need and desire in the art.